Chapter 10 Metastatic sarcomas, melanoma, and other non-epithelial neoplasms
INTRODUCTION
Malignant effusions caused by non-epithelial neoplasms are more frequently encountered in children than in adults. The most common causes of malignant effusions in children are lymphoma and leukemia, followed by non-epithelial neoplasms including Wilms’ tumor, neuroblastoma, Ewing’s sarcoma, and embryonal rhabdomyosarcoma.GENERAL CYTOLOGY
Only a few studies have described the cytologic examination of exfoliated sarcomas in effusion fluids.6,17,20 In general, due to the surface tension from the surrounding fluid, they have a tendency to round up and lack tissue arrangement, and the vascular or stromal pattern observed in fine-needle aspiration (FNA) specimens. Most metastatic sarcomas in the fluids are sparsely cellular, arranged either singly or in loose clusters (Table 10.1). The sarcomatous cells have indistinct cytoplasmic borders, and may show bipolar cytoplasmic processes. Binucleation or multinucleation may be present. The nuclei are usually round, oval, and sometimes fusiform or spindle-shaped. The nuclei demonstrate irregular contours, often with nuclear membrane infolding, chromatin clumping with parachromatin clearing, and prominent nucleoli. Nuclear details are better appreciated on ThinPrep preparation due to the monolayer arrangement of cells obtained with this method.16 Mitotic figures may be observed in high-grade sarcoma.
An additional helpful feature in these tumors is the background. Most sarcomas have a proteinaceous background with lysed blood and a few inflammatory cells.19 ThinPrep preparations tend to have a cleaner background, but in cases with tumor diathesis, the background is not altered by the technique. The mucoid matrix background in myxoid sarcomas is better appreciated in the cell block sections by Alcian blue at pH 2.5 but not by mucicarmine stain.19 It is more important to type the tumor cells as metastatic and predict their sarcomatous origin rather than subclassifying them.
ANCILLARY STUDIES
Ancillary studies such as immunohistochemistry (see Chapters 5, 15), electron microscopy, flow cytometry, and cytogenetics (see Chapter 13) have been employed for characterization of metastatic sarcomas in serous effusions. The ‘subtractive coordinate immunoreactivity pattern’ (SCIP) approach facilitates proper identification and interpretation of neoplastic cells in effusions (see Chapter 5, Figures 5.1Z, 5.4).
With the exception of synovial sarcomas and epithelioid sarcomas, most other sarcomas are negative for epithelial markers such as cytokeratin (Figure 10.3) and epithelial membrane antigen (EMA). HMB-45 immunostain and newly reported immunomarkers including Melan-A, MART-1 and tyrosinase are useful in distinguishing melanoma from sarcomas. S-100 protein is immunoexpressed in liposarcomas, chondrosarcomas, and sarcomas with neural differentiation. Muscle markers such as myoglobin, desmin, smooth muscle actin (SMA), and muscle specific actin (MSA) are helpful in identifying rhabdomyosarcoma and leiomyosarcoma.22 Nuclear positivity for MyoD1 is observed in tumors with striated muscle differentiation (such as rhabdomyosarcoma) with high sensitivity.20,25 However, many sarcomas do not exhibit a specific immunophenotype. Therefore, specific typing of these tumors in serous effusions should be based predominantly on clinical correlation.
Figure 10.3 Immunohistochemical and cytogenetic analysis of spindle cell tumors in effusions*. CG, cytogenetics; MPNST, malignant peripheral nerve sheath tumor.* Past history of the tumor is usually present. Rarely some tumors, such as angiosarcoma and synovial sarcoma, may present as primary tumor of the serous cavities.55–57
SARCOMAS
BLUE CELL TUMORS
Small blue cell tumors are a subgroup of tumors that are cytologically indistinguishable and may create a diagnostic dilemma. The use of immunohistochemistry on cell block material and cytogenetics can enhance the precision of interpretation (Figure 10.1).
Rhabdomyosarcoma
Rhabdomyosarcoma is the second most common soft tissue sarcoma, often in children under 15 years of age. It is the most common tumor of adolescents and young adults and is rare in patients older than 40 years. There are four major histological subtypes: embryonal, botryoid, alveolar, and pleomorphic (Table 10.2). The most common sites of metastasis are the lung, heart, and lymph nodes. Intraperitoneal spread of the rhabdomyosarcoma is estimated to occur in 7% of cases.27 Cytologic material from pleural, peritoneal, and pericardial fluids may be diagnostic in a pediatric population with the help of other ancillary studies.
Embryonal rhabdomyosarcoma
This subtype of rhabdomyosarcoma accounts for approximately 70–80% of all the rhabdomyosarcomas.5 The most common site of occurrence is head and neck followed by genitourinary and extremities.5 Embryonal rhabdomyosarcoma shows aggregates of small cells, which are about 2–5 times the size of mature lymphocytes. Also scattered large isolated cells with conspicuous perinuclear clearing are seen on both Giemsa and Papanicolaou (PAP) stains. The nuclei are hyperchromatic, enlarged, and pleomorphic. The cytoplasm is somewhat bubbly with indistinct borders. In Diff-Quik (DQ)-stained smears, the cells appear poorly differentiated and blast-like. Embryonal rhabdomyosarcoma is usually categorized under small blue cell tumors. Immunohistochemical stains are helpful to differentiate it from other small blue cell tumors (Figure 10.2). Occasionally, varying numbers of well-differentiated rhabdomyoblasts are seen as large, round, bizarre or strap cells with cross striations, are seen. These cross striations are specific for diagnosis of rhabdomyosarcoma, but are present only in 30% of cases. Rhabdomyosarcomas can occur in the setting of a sarcomatous transformation in patients with germ cell tumors or malignant mixed müllerian tumors of the ovary or endometrium.
Alveolar rhabdomyosarcoma
Alveolar rhabdomyosarcoma is the second most common subtype in childhood. On PAP stain, the smears are cellular with a mixture of reactive mesothelial cells and scattered rare single, bizarre dyscohesive, pleomorphic giant tumor cells in an exudative background. Mitotic figures are easily identified. The cytoplasm is eosinophilic, moderate, and sometimes vacuolated. The tumor cells demonstrate strong cytoplasmic positivity for desmin and a diffuse nuclear positivity for MyoD1 (see Figure 10.2).
Neuroblastoma
Neuroblastoma is the third most common malignant tumor and is the most common extracranial solid tumor in children. Neuroblastoma and related tumors are derived from the primordial neural crest cells that migrate from the mantle layer of the spinal cord and populate the primordia of the sympathetic ganglia and adrenal medulla.27 The age of presentation ranges from 2 months to 5 years, with a peak incidence at 18 months. The distribution of neuroblastomas follows the sympathetic chain and can arise anywhere from base of skull to pelvis, including adrenal medulla and dorsal root ganglia. About 90% of the neuroblastomas have elevated levels of catecholamines. The measurement of these metabolites in the urine is useful in monitoring the course of the disease. The incidence of pulmonary involvement at the time of diagnosis is low, averaging about 4% in children over 1 year old with stage IV neuroblastoma.27
In a report by Cowie et al, the incidence of a pleural disease or pleural effusion in a group of 1245 patients with neuroblastoma was 0.7%.31 Malignant effusions in the pediatric population are mostly the small blue cell type, predominantly lymphomas followed by neuroblastoma and germ cell tumors and sarcomas.30
Cytologically, the neuroblastomas are composed of rosettes, which are mostly retained in the effusions as well. The cytoplasm is scant with salt and pepper type chromatin. Ganglion cells are seen with maturation. An immunohistochemical panel can be used on cell blocks to differentiate neuroblastomas from other small blue cell tumors. Neuron-specific enolase (NSE) is commonly used to identify neuroblastic as well as neuroendocrine tumors.26 However, it is relatively non-specific and is expressed in other small blue cell tumors like Ewing’s sarcoma/peripheral neuroectodermal tumor (EWS/PNET) and desmoplastic small round cell tumor (DSCRT) as well.26
Chromosomal abnormalities like del 1p have been recognized as independent prognostic factors in the prognosis of these tumors.27 N-myc amplification has been recognized as another independent prognostic marker and is expressed in 30% of advanced-stage disease, as compared to 5% of earlier stage disease.27
Wilms’ tumor
Wilms’ tumor (WT), a pediatric renal malignancy, is the most common solid tumor in children. The prediction of outcome is based mainly on histology and the stage. Relapse in these tumors occurs within 4 years of initial presentation, and the common site of metastasis is lung.31
Pleural effusion at the time of presentation of the tumor is very rare and is not associated with adverse prognosis.31 WT comprises about 9% of total positive malignancies in the fluids.53
Histologically, the tumor is heterogeneous with epithelial, stromal, and blastemal components.27 The predominance of one of the components may be a diagnostic challenge, especially in a metastatic setting. A rare case of metastatic WT with an epithelioid pattern is described in bone.37 The cytology of WT in effusions is rarely reported in the literature.53
Immunohistochemistry is helpful to distinguish these tumors from other small blue cell tumors. WT-1 or Wilms’ tumor gene is a protein expressed in the developing kidney, in the differentiation of genitourinary organs.33 A strong expression of WT-1 is demonstrated in epithelial and blastemal components, whereas the stromal components only show vimentin immunoreactivity. Undifferentiated blastemal components show vimentin immunoreactivity; well-differentiated blastemal components show vimentin as well as cytokeratin immunoreactivity.26 Molecular aberration of chromosome 11p, where the WT-1 gene is located, is a useful adjuvant in establishing the diagnosis in these tumors.
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